Psychiatry News

After antidepressant treatments are discredited, fears grow that other products may be ineffective

by Jeremy Laurance

The pharmaceutical industry came under assault from senior figures in medical research yesterday over its practice of withholding information to protect profits, exposing patients to drugs which could be useless or harmful.

Experts criticised the stranglehold exerted by multinational companies over clinical trials, which has led to biased results, under-reporting of negative findings and selective publication driven by the market, which was worth £10.1bn in the UK in 2006, amounting to 11 per cent of total NHS costs.

The latest attack was triggered yesterday by an analysis of published and unpublished trials of modern antidepressants, including Prozac and Seroxat, showing they offer no clinically significant improvement over placebos (dummy pills) in most patients. But doctors said patients on the drugs should not stop taking them without consulting their GPs.

It was the first time researchers – from the UK, Canada and the US – had successfully used freedom of information legislation to obtain all the data presented to regulators when the companies applied to license their drugs. In some cases it had not been made public for 20 years. Over the past two decades the drugs, known as selective serotonin re-uptake inhibitors (SSRIs), have been among the biggest selling of all time, earning billions of pounds for their makers. Yesterday's finding suggests that the money may have been misspent. Drug companies are required by law to provide all data on a drug, published and unpublished, to the regulatory authorities when applying for a licence. But this requirement does not apply to the National Institute for Health and Clinical Excellence (Nice), which assesses cost effectiveness and recommends which drugs should be used by the NHS.

Peter Littlejohns, the clinical and public health director of Nice, said: "The regulatory authorities have access to everything. Obviously we have access to the published data and we do ask the industry for unpublished data, but it is up to the companies whether to deliver it or not. We have no power to demand it. The issue is that it relies on the good will of the industry."

Professor Mike Clarke, the director of the UK Cochrane Centre, an international collaboration between researchers in 100 countries which has published more than 3,000 systematic reviews of published trials to establish best medical practice, said lack of co-operation from the drug industry was damaging medical care. "When we ask for details of a trial the company might tell us nothing. We have even less power than Nice. Researchers trying to make sense of trials for decision-makers need to have access to this data. If we have only got access to half of the data, when we see evidence that a drug works we don't know whether to believe it or not. It makes us doubtful – that's the big worry. The companies are in the business of making profits – but they are also in the business of providing safe, effective health care."

Legislation to compel the drug industry to publish its results was included in Labour's manifesto at the 2005 election and last month the Commons Health Select Committee demanded that Nice be given unfettered access to all clinical trial results.

Yesterday, the Government said it had been told that compelling the industry to publish trial data would not be allowed and it was instead pursuing a voluntary approach, developing a "searchable register" of all trials that have taken place in the UK and pressing the EU to make its own confidential register public.

A spokesman for the Department of Health said: "The Government has consistently supported open access to information about research when the findings could affect decisions about treatment or health outcomes. We planned to support the principle of mandatory registration of clinical trials in the UK, but legal advice stated this would be illegal under EU law." A World Health Organisation working group is examining how to improve reporting of clinical trials and is expected to announce a consultation shortly.

The pharmaceutical industry was unrepentant about its strategy yesterday. Richard Tiner, the head of medicines at the Association of the British Pharmaceutical Industries, said: "The regulatory authorities have access to all the data – absolutely everything. Nice is not a regulatory authority – it is making decisions on whether medicines should be available on the NHS... There is no reason why the companies would restrict access – it depends what they are asked for. The industry is very much more transparent than it was 10 years ago."

GlaxoSmithKline, maker of Seroxat, said yesterday it "fully endorsed public disclosure of all clinical trial results" and had published all data relating to Seroxat on its website "regardless of study outcome".

The Antidepressant Debate

Paul Bough, 41: 'You name it, I've tried it: none of them worked'

"The findings of this latest report don't surprise me in the slightest. In fact, they confirm what I already knew. I've been a depressive for most of my life, and all of my adult life. After the umpteenth failed suicide attempt seven years ago my doctor said I should try taking antidepressant drugs. You name it, I've tried it. Diazepam, Citalopram, Prozac, Seroxat, Atenolol [a beta-blocker], Effexor: none worked. They turned me into a zombie, totally incapable of motivation or movement and forced to vegetate on a sofa. I'd say to anyone on these drugs, you're better off going cold turkey. Talk to people, have therapy, be sociable: but don't rely on these little happy pills. Having tried the lot, I'm coming off – and staying off."

Sylvia Genge, 59: 'Without these drugs I would lose hope altogether'

"The findings go against several decades of experience. I have suffered three major traumas in my life – my father leaving home when I was 11, my husband having an affair, and now an unpleasant divorce – and I'm convinced these drugs helped me survive them. I've been close to suicide myself, but now, in my 60th year, I'm feeling positive and able to survive all the terrifying experiences each day throws at me. I take 20mg of Fluoxetine each day, and it makes me feel I can cope. I simply don't buy the idea that it's just a placebo – but then I suppose the point is even if it were I wouldn't care. These drugs are my crutch and my comfort; without them I would lose hope altogether. I'm staying on."

In the research literature drugs are not referred to by brand names. In the context of rigorous attention to scientific data, as opposed to the world of sales and marketing, using trade names would suggest influence by commercial pressures, which would call into question the investigator's independence and objectivity. Shouldn't independence from commercial pressures be just as important in the clinical world? But, surprisingly, in day-to-day practice nobody seems to be at all concerned about this. Everyone — physicians, pharmacists, patients, insurance companies — seems to use brand names to refer to medications. I see this as directly related to the pervasiveness of pharmaceutical company marketing and I believe it is a serious problem. Part of the problem is that no one recognizes it as a problem. Look at how fundamentally our thinking is affected. The alternative to using the brand name is to use the "generic" name, right? But this term in itself is misleading: what we call the "generic" name of the drug is actually the name of the drug! "Zoloft" was in fact a brand of the drug sertraline from the beginning, but everyone acts as though "sertraline" came into existence only after the patent on "Zoloft" expired. (Many people refer to sertraline as "generic Zoloft.") With older drugs our thinking is clearer — we don't think of aspirin as "generic Bayer," it's aspirin, and "Bayer" is one brand. It is remarkable that even doctors and pharmacists are often confused about this, and that it needs clarifying. Try ordering a new drug still on patent by its actual name and you're likely to get "I didn't think that had gone generic yet." Actually, it's worse than that. I recently tried to order simvastatin from a mail order pharmacy and was told they didn't carry it — one of the dozen most prescribed drugs in the country! It took three people 10 minutes of searching around before I was told that they had "Zocor," however! A national mail-order pharmacy, and they didn't list the drug under its actual name — nor did anyone even seem to know the actual name of the drug! "Tissues, tissues... let's see.... Hmmm, I guess we don't carry tissues.... Oh, wait — we have Kleenex, is that what you want?" Brand name drug marketing is by far the biggest product promotion success in the whole world of commercial enterprise, because the primary brand names have not just become synonymous with the actual names of the drugs, they have replaced the actual names of the drugs. Adofen, Affectine, Alzac, Ansilan, Deproxin, Erocap, Fluctin, Fluctine, Fludac, Flufran, Flunil, and 27 other trade names besides the one everybody knows — all are brands of fluoxetine, but even pharmacists still call the stuff "Prozac." Imagine how the marketing folks at GM would be rubbing their hands with glee if everyone referred to their Toyotas and Hondas and Fords and Subarus as "Chevys!" These habits are very deeply ingrained. For instance, remember that each nation handles its own trademarks and patents, so brand names are local to a specific country. On the psychopharmacology mailing list — a listserv that has over 1000 subscribers from all over the world — American psychopharmacologists routinely refer to "Celexa" and "Trileptal" and "Remeron" despite constant reminders that these names are unknown to prescribers in England, Indonesia, Turkey, Australia, Brazil, South Africa, etc. I have seen the periodic notice about not using brand names go out from the list moderator (as it has regularly for years) and the very next day someone from the US posts a comment mentioning "Luvox," prompting a follow-up question from a member in Japan politely asking what Luvox is. It is remarkable that even in a group of medical professionals, in a context in which it has a direct and personal impact on successful communication, and in the face of constant reminders, people still can't wake up to what they are doing. Judging by the psychopharm mailing list, this seems to be especially problematic in the US. Note that Luvox is a particularly illuminating example, since the original manufacturer of fluvoxamine no longer makes this drug. Thus, there is actually no "Luvox" on the market any more. But try referring to it as fluvoxamine and see how many blank stares you get until you say, "You know... Luvox." What is so insidious is that everyone seems completely unaware that there is a problem here. The health care system and the public have been hypnotized by the drug companies. I use the word deliberately: the methods used are classic hypnotic techniques. With doctors, the drug reps first establish a context of support and nurturance — gifts of "Cymbalta" pens and notepads, sandwiches — and then they set up a discussion that embodies a further distraction: they show us data on Cymbalta. We say, but what's the difference between Cymbalta and Effexor, they respond with more data about noradrenergic effects at low doses, we're partially convinced but a bit skeptical, etc. We think that we are being objective, that we're sophisticated enough to critically evaluate the data on Cymbalta and thus are immune to bias — and all the while the real marketing agenda succeeds brilliantly: we're talking about "Cymbalta," not about duloxetine. Cymbalta, Cymbalta, Cymbalta, Cymbalta. A lot of us end up a little fuzzy about what duloxetine is. ("Oh, you mean Cymbalta!") I am convinced that this is one of the big reasons the drug companies find it worth their while to spend collectively over $11,000 per doctor per year on detailing: in between bites of "complimentary" chicken pesto panini they train us in a language and a habit of thinking. And we doctors remain completely unaware of what we have bought into and then talk to our patients and each other using exclusively brand names — the language that we learn from the drug reps — thereby teaching our patients how to think and talk about meds. All this is now reinforced by direct consumer marketing: "Ask your doctor if Paxil is right for you!" Patients begin requesting "Paxil," and after the original patent expires some will say, "I don't want that generic stuff, I want Paxil." And we write prescriptions for "Paxil." And the shareholders are happy. I think that a doctor should be somewhat embarrassed to use brand names in talking about medications. It suggests that her/his primary source of information about meds is the drug rep rather than the medical literature. It shows that s/he is not involved first and foremost in assessing the research data. When I use the actual names of the drugs instead of brand names, my viewpoint changes — the language reminds me that my position is that of an applied scientist, that my job is to weigh all the information available and make judgments about what is best for my patient based exclusively on the evidence, not on the pitch of a salesperson. It has occurred to me more than once when talking with a drug company representative that I could say, "OK, I'll refer to olanzapine as 'Zyprexa' if you pay me for advertising your product each time I do it." But that would be grossly unethical, wouldn't it? Well, is it less unethical for me to do it for free? (Or for "free" lunches and pens and notepads and clocks and letter-openers and mugs?) So I'm stubborn in fighting this. I'll endure the puzzled pause of a pharmacist when I phone in a refill for escitalopram — though, sadly, to be certain that they get the prescription right I usually have to add, "You know... Lexapro." I try to teach my patients the names, not just the brands, of the meds I prescribe them. I refuse to be a marketing tool. The drug companies may be taking over the world, but they're not going to take over my mind

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